Neurofibromatosis (NF) is a common human autosomal dominant condition characterized by cafe-au-lait spots, neurofibromas, and a broad range of other manifestations. Its high spontaneous mutation rate (among the highest described in man) and preliminary linkage analysis using protein polymorphisms has suggested that the responsible mutation may be at a different locus in different families. The power of linkage analysis to identify the location of a mutant gene has recently been greatly extended by the introduction of DNA polymorphisms as genetic markers, which should allow any disease gene to be mapped if appropriate families are available for study, and if a sufficient number of informative markers can be generated. NF is a highly appropriate target disorder for this approach. We propose to ascertain three or four three-generation families with NF and sufficient available family members to allow linkage analysi on single families, so that potential locus heterogeneity will not destroy any associations. Using EB virus transformed lymphocytes, we will look for evidence of linkage to GC blood group (chr. 4) and secretor (chr. 19) both of which have been suggested to show linkage to NF in some but not all families. We will also develop and study markers on chromosome 8 (where circumstantial evidence suggests the NF locus might be, and for which DNA probes are needed anyway). We will maximize the rapidity of obtaining linkage information on other autosomal chromosomes by using probes for multigene families, as well as the "minisatellite" probes recently described which detect a large family of polymorphic markers on a single Southern blot.